Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice

Abstract

Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17β-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment.

Revealing mechanism of Methazolamide for treatment of ankylosing spondylitis based on network pharmacology and GSEA

“…In 2017, Hyemin Jeong et al reported that estrogen could attenuate the spondylarthritis manifestations of the SKG arthritis model 70 . Later, they also applied selective estrogen receptor modulator lasofoxifene to suppress joint inflammation and enhance bone mineral density in zymosan-induced SKG mice 71 . Furthermore, oral estrogen therapy in female patients and human chorionic gonadotrophin injections in male patients with AS could result in a moderate clinical improvement 72 .…”

Ankylosing Spondylitis Pathogenesis and Pathophysiology

“…One report proposed ostrogens might reduce arthritis due to their suppression of wnt signalling [72]. Another study reported that selective oestrogen receptor modulator (SERM) lasofoxifene not only suppresses the effects of joint inflammation and improves bone mineral density in SKG mice, but it also affected the composition and biodiversity of the gut microbiome, with the authors concluding further reaserch on the role of SERMS to evaluate their effects in SpA is required [73].…”

“…There is literature to suggest a relationship between women who experience excess androgen levels in conditions such as polycystic ovarian syndrome (PCOS) and development of AS [74], as well as other rheumatic diseases [75]. A Korean study questioned whether other factors besides sex hormones play a role in reduced disease progression in females noting in their study there was no significant relationship between oestrogen levels and radiographic progression [73].…”

Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice

“… 20 Previously, SERMs have been reported to modulate inflammation in animal models of IBD, 21 , 22 autoimmune encephalomyelitis, 23 , 24 and ankylosing spondylitis. 25 Additionally, clinical data suggests that tamoxifen may decrease C‐reactive protein levels in healthy females. 26 …”